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PubMed1986

Effect of dihydroergotamine on +Gz acceleration tolerance.

Dihydroergotamine is a potent vasoconstrictor of the venous capacitance vessels and has been shown to decrease blood pooling in patients with orthostatic hypotension. Acceleration acting on the long axis of the body (+Gz) pools blood into the lower body of the subject. Nine healthy men received an injection of 1 mg dihydroergotamine and 1 ml of saline intramuscularly in a randomised, double blind fashion, and had their Gz acceleration tolerances measured. Dihydroergotamine significantly increased Gz tolerance by 0.24 G and narrowed the difference between the maximum heart rate during the acceleration epoch and resting baseline by 10%. The drug had no effect on blood pressure and heart rate when the subjects changed from the supine to standing position. The increase in Gz tolerance was not sufficient for operational use.

Acceleration↗
PubMed2004

Tolerance to response-disruptive effects of cocaine is facilitated by opportunity to respond in the absence of drug.

A dose of cocaine that was 1/8 of a logarithmic unit larger than the smallest dose that produced complete suppression of responding of pigeons under a fixed-ratio 20 schedule was administered prior to 50 daily sessions. If responding occurred, then the dose was increased by 1/8 of a logarithmic unit and administered for an additional 50 sessions. The pigeons were divided into either a 'control' or 'saline' group. Control group pigeons received the same dose of cocaine for 100 additional days. Pigeons in the saline group were also exposed to a daily dosing regimen for 100 more sessions except that saline was substituted once every 5 days. Daily dosing then continued and dose-response functions were re-determined by substituting other doses for the daily dose every fifth session. During the first exposure to each dose, tolerance was evident for five of six pigeons in the saline group, whereas sensitization was evident for pigeons in the control group. Tolerance was observed in both groups following subsequent exposures. Tolerance to effects of behaviorally large doses of cocaine was therefore promoted when saline was occasionally substituted for the daily dose. Opportunity to respond during an ongoing regimen of daily cocaine administration enhanced the development of tolerance.

Animals↗
PubMed1993

Time course and magnitude of tolerance to the analgesic effects of systemic morphine in amphibians.

The systemic administration of morphine (100 nmol/g, s.c.) produced a significant and long-lasting analgesia (up to 8 h) in the Northern grass frog, Rana pipiens. Daily bolus injections of the same dose of morphine or saline for one week resulted in a significant analgesia for 3 days in the morphine group, which fell to levels indistinguishable from the saline-treated controls on days 4 through 7. In separate experiments, animals were treated identically with morphine or saline but were not tested daily for pain thresholds. In these animals, administration of a range of morphine doses on day 8 yielded dose-response curves significantly-shifted rightward by a factor of 3.3 in the morphine-treated group compared to the saline-injected controls. These studies are the first to show the time course of tolerance development and the magnitude of morphine tolerance in a non-mammalian vertebrate species.

Animals↗
PubMed1976

Investigation of occurrence of tolerance to bronchodilator drugs in chronically pretreated guinea-pigs.

1 The actions of sympathomimetic amines on isolated preparations of atria, trachea and ileum were studied in vitro in guinea-pigs, which had been pretreated for 5 or 12 days, by subcutaneous injection, with adrenaline (5 mug/kg), salbutamol (0.5 mug/kg), salbutamol (0.5 mug/kg), methoxamine (250 mug/kg) or saline (0.9% w/V NaCl solution). 2 In the trachea, a decrease in sensitivity (tolerance) to the relaxant effect of adrenaline was induced by pretreatment, for 12 but not for 5 days, with adrenaline. In these animals, cross-tolerance to isoprenaline or salbutamol was not observed. Tolerance to the relaxant actions of adrenaline isoprenaline or salbutamol was not observed after pretreatment with salbutamol. 3 In the trachea, pretreatment with methoxamine or adrenaline for 12 days did not change the sensitivity to the alpha-adrenoceptor-mediated contractor action of methoxamine. 4 In the atria from those guinea-pigs pretreated with adrenaline or salbutamol, there was no reduced sensitivity to the beta-adrenoceptor agonist actions of adrenaline, isoprenaline or salbutamol. In animals pretreated with methoxamine or adrenaline, there was no observable tolerance or cross tolerance to methoxamine with respect to its alpha-adrenoceptor-mediated positive inotropic action in the atria and no unequivocal evidence of a reduced sensitivity to that action of adrenaline. 5 It was confirmed that the twitch-like contractions of the longitudinal muscle of the electrically stimulated ileum were inhibited by sympatomimetic amines acting on alpha- and beta-adrenoceptors. There was no reduced sensitivity to the inhibitory actions of noradrenaline or isoprenaline on the twitch of ileum isolated from animals pretreated with adrenaline, salbutamol or methoxamine for 5 or 12 days. 6 From our results on these three preparations from the same animals, it is concluded that generalizations regarding changes in sensitivity to sympathomimetic amines following their prolonged administration should not be made in any one species.

Animals↗
PubMed1982

Enhanced arrhythmogenic activity of beta-adrenoceptor stimulants in desoxycorticosterone-pretreated rats.

The arrhythmogenic activity of four beta-adrenoceptor stimulants, metaproterenol, salbutamol, isoetharine, and dobutamine, was determined in adult, Wistar rats pretreated for 3-4 weeks with desoxycorticosterone (DOCA) and 1% saline as drinking fluid. Doses (SC) of these stimulants which were well tolerated in untreated animals elicited severe ventricular dysrhythmias, often leading to death in ventricular fibrillation. The LD50 in mg/kg was as follows: metaproterenol, 0.28; salbutamol, 0.60; isoetharine, 2.3; and dobutamine, 4.8. The relative potency of metaproterenol, salbutamol, and isoetharine correlates well with their ability to stimulate beta 1-adrenoceptors. It is suggested that DOCA-saline pretreatment in rats may be used as a model for the rapid screening of drugs affecting beta-adrenoceptors.

Adrenergic beta-Agonists↗
PubMed1992

Adrenalectomy reverses chronic injection-induced tolerance to nicotine.

A recent study from our laboratory has demonstrated that C57BL/6 male mice that are chronically injected with nicotine develop a profound tolerance to nicotine that is not associated with changes in brain nicotinic receptors. We have proposed that alterations in the secretion of corticosterone (CCS) may regulate tolerance development in chronically injected animals. In the present study we have directly tested this hypothesis. Female DBA/2 mice were injected three times each day for 12 days with saline or 2 mg/kg nicotine. Blood samples were collected at various time points during the course of treatment and plasma CCS levels were determined. The animals were divided into two groups following the last injection on day 12. The first group of animals was tested for nicotine-induced release of corticosterone on day 13 of the experiment and then sacrificed. The brains of these animals were subsequently used to measure nicotinic receptor binding. The second group of animals was adrenalectomized (ADX) or sham-operated on day 13 of the experiment and tested for nicotine sensitivity on day 14 of the experiment. Plasma CCS levels were significantly elevated in animals that were chronically injected with nicotine (versus saline controls) by the fourth day of the experiment. Chronic nicotine-injected animals were tolerant to nicotine-induced CCS release. Animals that were chronically injected with nicotine and sham-operated were tolerant to acute nicotine challenge; however, tolerance to nicotine was not detected in ADX animals. These data support the hypothesis that the capacity to release CCS may underscore the expression of tolerance to nicotine in chronically injected animals.

Adrenal Glands↗
PubMed1989

Psychrometric pressure-volume analysis of osmoregulation in roots, shoots, and whole sporophytes of salinized ceratopteris.

Osmotic and turgor adjustment in roots, shoots, and whole sporophytes of a NaCl-tolerant mutant and a NaCl-sensitive wild-type strain of the fern Ceratopteris richardii Brongn. were characterized following exposure to 60 millimolar NaCl, using a psychrometric approach to pressure-volume analysis. Water potential components of whole plants and shoots at full or ambient hydration were similar between strains. Roots of the mutant, however, had osmotic potentials at full turgor and water potentials at zero turgor which were lower (0.32 and 0.46 megapascal, respectively) than those in roots of the wild type after salinization. Although compromised in the absence of NaCl, sporophytes of the mutant strain were larger and much less necrotic in 60 millimolar NaCl after 17 days, compared to the wild type. Root growth in the mutant strain was unaffected by salinization and far exceeded root growth in the wild type. Correlation coefficients of the linear regression and the general consistency and precision of the pressure-volume data demonstrated the feasibility of using PV curves for estimating water potential components of roots. The technique should also provide a means of studying osmoregulation in a variety of other rapidly equilibrating plant tissues.

Journal Article↗
PubMed1998

Learned tolerance to ethanol-induced c-Fos expression in rats.

With c-Fos immunoreactivity as a marker for neural activity, we examined whether environmental cues associated with ethanol injection influence the expression of tolerance to ethanol-induced c-Fos activation. Over 24 training days, male Long-Evans rats received ethanol injection (2.5 g/kg) in one environment and saline injection in a different environment. Relative to rats that received ethanol for the first time, ethanol-induced c-Fos expression in the paraventricular nucleus of the hypothalamus (PVN) and the locus coeruleus (LC) was significantly reduced in rats that had received multiple prior ethanol administrations. However, tolerance was partially reversed when ethanol was given in the saline-paired, rather than the ethanol-paired, environment. Results suggest that tolerance to ethanol, as indexed by c-Fos expression in the PVN and the LC, is mediated in part by Pavlovian conditioned responses to cues that predict ethanol administration.

Animals↗
PubMed1994

Enhanced susceptibility of the immune system to stress in morphine-tolerant rats.

The purpose of the present study was to determine the potential consequences to the immune system of the combined exposure of rats to stressor and morphine. Within 30 min following either morphine (5 mg/kg) injection or restraint stress (30 min) maximal analgesic responses as measured by tail-flick assay were observed. However, only morphine treatment was accompanied by a significant suppression (50%) in mitogen-stimulated lymphocyte proliferative responses. Restraint stress for either a 30-min or 2-h duration had no effect on lymphocyte responses. Exposure to a combination of restraint stress and acute morphine (5 mg/kg) resulted in a 50% suppression of lymphocyte responses which was similar in magnitude to that observed with morphine administration alone. When rats were injected twice daily for 4 days with increasing doses of morphine ranging from 10 mg/kg to 40 mg/kg, morphine (10 mg/kg) administration on Day 5 was not accompanied by either analgesia or depressed blood lymphocyte proliferative responses. These results indicated that tolerance had developed to both the analgesic and the immunosuppressive effects of morphine. However, upon exposure of morphine-tolerant animals to restraint stress, significant analgesic responses were retained. Furthermore, in contrast to the lack of suppression following restraint stress on lymphocyte responses in saline-injected animals, restraint for 30 min produced greater than a 70% suppression in morphine-tolerant animals. These data suggest that morphine tolerance may be accompanied by an enhanced susceptibility to the immunosuppressive effects of stress.

Analgesia↗
PubMedDate not supplied

The induction of immunologic tolerance with type III pneumococcal polysaccharide cross-linked or coupled to protein.

Type III pneumococcal polysaccharide molecules were linked to one another, i. e. cross-linked. The product was essentially insoluble in saline. Large pieces weighing 1-2 mg were inserted into mice. They produced immunologic paralysis or immune tolerance. When placed intraperitoneally in millipore chambers the cross-linked polysaccharide did not have any apparent effect, for the mice were not tolerized. When pneumococcal polysaccharide was linked to a protein, the amount of polysaccharide required to cause tolerance or immunity was essentially the same as the amount of free pure soluble polysaccharide. In addition, Xenopus laevis eggs were injected with a different antigen, bovine gamma globulin, and then with antibody to that antigen. Twelve of the twelve eggs so injected changed shape. Equal numbers of other eggs injected twice with the antigen or twice with the antibody did not change shape.

Agglutinins↗
PubMed1999

Extracellular fluid restoration in dehydration: a critique of rapid versus slow.

We compared current recommendations for treatment of severe dehydration by World Health Organization physicians and by the American Academy of Pediatrics Committee on Pediatric Gastroenterology with those in general textbooks of pediatrics, written mostly by pediatric nephrologists. The former recommend rapid (1- to 2-h) and generous intravenous restoration of extracellular fluid (ECF) volume followed by oral rehydration therapy (ORT) to replace potassium, current maintenance, and diarrheal losses--the rapid rehydration regimen. Oral feedings usually are resumed in 8-24 h. General textbooks of pediatrics usually recommend giving 20 ml/kg saline "to restore circulation," followed by the deficit therapy regimen to correct serum electrolyte abnormalities and replace remaining deficits of water, sodium, chloride, and potassium over 1-2 days. Mortality for hospitalized patients with dehydration treated with rapid rehydration was <3 per 1,000; no recent results are reported for patients treated by deficit therapy. The rapid rehydration regimen improves patient well being and restores perfusion, so that oral feedings are readily tolerated and renal function corrects serum electrolyte abnormalities in 6 h. Amounts of saline given correspond to amounts given for treating various forms of shock. Deficit therapy regimens provide less ECF restoration and are slower at restoring perfusion; tolerance for oral feedings is delayed. Two hundred pediatric nephrologists were surveyed, asking how they would treat a patient with severe dehydration and a patient with 40% burns. Only 30 of 200 responded; 29 used a deficit therapy regimen, with 20-40 ml/kg ECF replacement, while a majority rapidly and generously restored ECF volume in burn shock. We recommend that fluid therapy chapters should stop teaching deficit therapy for treating severe dehydration and instead teach the rapid rehydration regimen.

Child↗
PubMed1986

On the mechanisms of the development of tolerance to the muscular rigidity produced by morphine in rats.

The development of tolerance to the muscular rigidity produced by morphine was studied in rats. Saline-pretreated controls given a test dose of morphine (20 mg/kg i.p.) showed a pronounced rigidity recorded as tonic activity in the electromyogram. Rats treated for 11 days with morphine and withdrawn for 36-40 h showed differences in the development of tolerance: about half of the animals showed a rigidity after the test dose of morphine that was not significantly less than in the controls and were akinetic (A group). The other rats showed a strong decrease in the rigidity and the occurrence of stereotyped (S) licking and/or gnawing in presence of akinetic or hyperkinetic (K) behaviour (AS/KS group), suggesting signs of dopaminergic activation. The rigidity was considerably decreased in both groups after 20 days' treatment. In a further series of experiments, haloperidol (0.2 mg/kg i.p.) was used in order to block the dopaminergic activation and to estimate the real degree of the tolerance to the rigidity without any dopaminergic interference. Haloperidol enhanced the rigidity in the A group. However, the level in the AS/KS group remained considerably lower than in the A group. The results suggest that rigidity, which is assumed to be due to an action of morphine in the striatum, can be antagonized by another process leading to dopaminergic activation in the striatum. Nevertheless, there occurs some real tolerance to this effect. The rapid alternations of rigidity and the signs of dopaminergic activation observed in the animals of the AS/KS group might be due to rapid shifts in the predominance of various DA-innervated structures.

Animals↗
PubMed1987

Investigation of tolerance to chronic intrathecal morphine infusion in the rat.

Rats received chronic subcutaneous or intrathecal infusions of either saline or 25 micrograms/microliter/hr or 50 micrograms/microliter/hr of morphine sulfate. During five days of infusion individual groups of rats were assessed on either the nociceptive tail flick or hot plate test. After the infusions, the analgesic effects of either subcutaneous or intrathecal morphine test doses were evaluated. Tolerance developed to the analgesic effect of both subcutaneous and intrathecal morphine infusions on the tail flick test. Subcutaneously infused rats were also tolerant to a subcutaneous morphine challenge on this test. However, intrathecally infused rats were not tolerant to either the subcutaneous or intrathecal challenge. In contrast to these results, rats tested on the hot plate were not analgesic in response to either subcutaneous or intrathecal morphine infusions. However, these rats were tolerant when challenged with either subcutaneous or intrathecal morphine. The results are discussed in terms of the relative contribution of spinal and supraspinal sites to opiate tolerance, and the possibility that tolerance does not develop to the antinociceptive effect of spinal morphine on spinally mediated reflexes.

Animals↗
PubMed1992

Contingent tolerance to the disruptive effects of alcohol on the copulatory behavior of male rats.

Sexually active male rats received five 30-min copulation tests with sexually receptive females, one every 4 days. One group of rats received alcohol (1 g/kg, IP) 45 min before, and an equivalent volume of saline 45 min after, each test; a second group received saline before and alcohol after each test; and a third, control group received saline both before and after. Four days after the last of the five tolerance-development trials, each rat received an injection of alcohol (1 g/kg, IP) 45 min before a copulation test so that the development of tolerance in the three groups could be compared. Tolerance to the disruptive effects of alcohol on mount, intromission, and ejaculation latencies, and on the duration of the postejaculatory interval was found to be significantly greater in the rats injected with alcohol before each copulation test than it was in the rats in the other two groups. These results constitute the first experimental evidence that tolerance develops to the disruptive effects of alcohol on male sexual behavior, and they support the theory that tolerance is an adaptive response to the disruptive effects of drugs on concurrent patterns of neural activity, rather than to drug exposure per se.

Animals↗
PubMed1999

The role of growth hormone and glucocorticoid in glucose handling in vivo.

Growth hormone (GH) can oppose the catabolic effects of glucocorticoids. However, both hormones have adverse effects on carbohydrate metabolism. Here we examined the interactive effects of GH and the glucocorticoid methylprednisolone (MP) on glucose tolerance, insulin resistance and [3H]2,6-deoxyglucose uptake of peripheral tissues in rats. Female Wistar rats received either saline, GH (2.7 mg/kg), MP (5.0 mg/kg) or GH+MP. After 7 days treatment, animals were subjected to an i.v. glucose tolerance test. In a second experiment, animals treated as above were anesthetized and injected with human insulin (0.5 U/kg), [3H]2,6-deoxyglucose (500 microCi/kg), and [14C]mannitol (25 microCi/kg), to estimate insulin resistance and [3H]2,6-deoxyglucose uptake in fat and muscle. Weight gain in controls was 7.6+/-1.7 g, while GH treatment increased the mean body weight by 18.7+/-2.2 g (P<0.0002) and MP inhibited weight gain down to 0.0+/-1.0 g (P<0.004). This drop in weight gain was reversed back to normal when GH was given in combination with MP. After a glucose tolerance test no significant differences in glucose area under the curve were detected when comparing individual groups with the control group, but samples taken just before this test revealed that basal insulin was significantly elevated in the group treated with GH (174+/-27 pM, P<0.008), or GH+MP (209+/-21 pM, P<0.004), when compared with controls (107+/-17 pM). MP alone had no effect (122+/-19, P<0.3). After an i.v. bolus of insulin the group receiving GH+MP had a significantly (P<0.007) higher level of circulating glucose compared with controls (6.5+/-0.3 mM vs 4.4+/-0.7 mM). Despite this, there were no differences in peripheral glucose uptake between the two groups. In conclusion this study shows that a combined administration of GH and MP decreases the potency by which insulin decreases circulating glucose levels, but that peripheral tissues are not primarily involved in this insulin resistance.

Animals↗
PubMed1987

Salinity stress induced tissue-specific proteins in barley seedlings.

Protein changes induced by salinity stress were investigated in two barley cultivars, California Mariout, a salt-tolerant variety and Prato, a salt-sensitive variety. Rapidly growing young barley seedlings were exposed to NaCl and the newly synthesized proteins were resolved on two dimensional polyacrylamide gels following isoelectric focusing or nonequilibrium pH gradient gel electrophoresis in the first dimension. Salinity induces distinct protein changes in root and shoot tissues. In roots, the salinity effects are identical in both cultivars. First, salinity modulates the synthesis of two different sets of proteins, one of which is elevated, and the other, depressed. Second, six new proteins are induced all of which are low in molecular weight, 24 to 27 kilodaltons, with an isoelectric point range of 6.1 to 7.6. In contrast to roots, salinity induces cultivar-specific shoot proteins. Five new shoot proteins are induced whose molecular weights and isoelectric points fall within the range of 20 to 24 kilodaltons and 6.3 to 7.2, respectively. Three of the newly induced proteins are unique to Prato. In addition, salinity inhibits the synthesis of a majority of shoot proteins. The new proteins produced in roots and shoots are unique to each tissue and their induction is apparently regulated coordinately during salinity stress.

Journal Article↗
PubMed2005

The role of potassium as an ionic signal in the regulation of cyanobacterium Nostoc muscorum response to salinity and osmotic stress.

Spontaneously occurring thallium-resistant (Tl+ -R) mutant of diazotrophic, heterocystous cyanobacterium Nostoc muscorum is described in which Tl+ -R phenotype is the cause of defective salinity-inducible K+ uptake activity and proline uptake activity. The results indicate that mutant strain is more sensitive to salinity and osmotic stresses than its parent. The mutational inactivation of salinity-inducible proline uptake was found associated with increased sensitivity of the cyanobacterial photosynthetic O2 evolution and nitrogenase activity under salinity and osmotic stresses. It is suggested that in the cyanobacterium Nostoc muscorum K+ functions as a primary osmolyte which is associated with salinity-inducible proline uptake leading to the acquisition of salt tolerance in the cyanobacterium.

Adaptation, Physiological↗
PubMed1983

Shift from inhibition to excitation in the neostriatum but not in the nucleus accumbens following long-term amphetamine.

Neuronal responses to 1.0 or 5.0 mg/kg D-amphetamine were recorded simultaneously in the neostriatum and nucleus accumbens of rats pretreated twice daily with these doses or with saline for 6 consecutive days. In all groups, the number of neurons responding to a challenge injection of either dose of amphetamine with an overall excitation or inhibition was not significantly different. During the first 30-60 min of the drug response, however, neurons in the neostriatum of amphetamine-pretreated rats responded with a significant increase in firing rate compared to saline controls. In the nucleus accumbens, on the other hand, tolerance developed to the inhibition produced by 1.0 mg/kg D-amphetamine, whereas the responses produced by 5.0 mg/kg were not significantly altered by long-term treatment. Liquid chromatography with electrochemical detection revealed that pretreatment with 5.0 mg/kg D-amphetamine produced a slight, but significant, reduction of dopamine and norepinephrine levels in the neostriatum. Catecholamine levels were not significantly altered in the nucleus accumbens by either dose. These electrophysiological and neurochemical changes are discussed in relation to the known involvement of these sites in the dose-dependent behavioral alterations that accompany repeated amphetamine injections.

3,4-Dihydroxyphenylacetic Acid↗